tbuckley/cabot-search huggingface dataset:
Pattern of disease progression amongst veterans with stage IV non-small cell lung carcinoma (NSCLC) on immunotherapy.
Authors: Fatima Mahmood, Amin Azem, Darren Gemoets, Vimala Thalody, Syed Arzoo Mehdi
Journal: Journal of Clinical Oncology (2022)

e21032 Background: Use of immune checkpoint inhibitors against advanced stage NSCLC is associated with significant reduction in overall morbidity and mortality. However, despite the survival benefit, tumors invariably relapse. We aim to study pattern of disease progression and assess baseline or tumor specific associations. Methods: We performed a retrospective review of 74 Veterans with Stage IV NSCLC who received ≥2 immunotherapy cycles between 2015-2021 at Albany Stratton VA Medical Center. IRB approval was obtained. Fisher Exact Probability Test was used to analyze data, level of significance at &lt; 0.05. Results: Baseline characteristics of 74 male veterans revealed median age 67 years (IQR 62.5-72.5). Common tumor histology included squamous cell carcinoma (SCC; n = 38, 51.3%) and adenocarcinoma (n = 32, 43.24%), PD-L1 expression &gt; 50% in 33.8% of population. Molecular testing positive for EGFR in 1 patient and otherwise negative for EGFR, ALK, BRAF, ROS, KRAS translocations in all patients. Treatment regimen was either immunotherapy alone or concurrent chemoimmunotherapy. Disease status prior to starting immunotherapy was classified as M1a (25.7%), M1b (50%) and M1c (24.3%). Out of total study population, progression of disease was noted in 48 patients (56.4%) further divided into progression at initial site only 20.8%, new site only 31.2%, or combined 48%. Most common sites of progression included local and distant LNs, brain, bone, and liver. Using Kaplan Meier Survival Analysis, median progression free survival (PFS) from start of immunotherapy till evidence of progression was 8.4 months. Our data revealed that progression at initial, new, and combined sites was noted in both adenocarcinoma and SCC. Use of immunotherapy as first line therapy and smoking history &gt; 50ppd were also associated with risk of progression. Other characteristics such as ECOG score (p = 0.50), initial metastatic status (p = 0.30), type of immunotherapy (p = 0.60) and PD-L1 score (p = 0.27) did not reveal significant association. We did not find any association between baseline characteristics and improved PFS. Conclusions: We conclude that certain baseline characteristics can be associated with progression of Stage IV NSCLC on immunotherapy amongst Veteran population. We recommend further studies with a larger study population to analyze the pattern of disease progression and associated factors. This will allow physicians to modify and personalize therapy regimen to improve PFS.[Table: see text]
Outcomes of Richter’s syndrome in patients with chronic lymphocytic leukemia (CLL) treated with platinum or anthracycline based chemotherapy with or without a BTK inhibitor (BTKi).
Authors: Maryam Alasfour, Georgios Pongas, Sandra Jones, Salman Alawadi, Thomas Plate
Journal: Journal of Clinical Oncology (2022)

e19511 Background: Richter’s syndrome (RS) is a rare complication of chronic lymphocytic leukemia (CLL) and the median survival is generally poor. Evidence is limited regarding the biology of the disease, treatment and outcomes. Methods: We retrospectively reviewed pts diagnosed (dx) with pathologically confirmed RS who presented at the University of Miami Sylvester Cancer Center between 2011 and 2020. Informed consent was provided through IRB-approved protocols. Descriptive statistics were utilized and overall survival (OS) was calculated from RS diagnosis to death or last follow-up by Kaplan-Meier. Results: 33 patients with RS, including 87.9% diffuse large B-cell lymphoma-type RS and 12.1% Hodgkin lymphoma-type RS were identified. Median time from CLL dx to RS transformation was 37months (m). Most patients presented with elevated LDH 75%, bulky lymphadenopathy 66%, and adverse genetic features, such as TP53 disruption 52% or complex karyotype 81%. FISH at RS dx: del(17p) 37%, del(11q) 17%, trisomy 12 58%. ORR to first line therapy was 75.8% (55% CR, 27% PR), but of those who achieved CR, 44% relapsed. Median PFS (mPFS) was 10m for the anthracycline-based chemotherapy group (ABC) with a CR of 50%, compared to 15.5 m for the platinum-based chemotherapy group (PBC) and a CR of 60%. Similar OS were observed regardless of the chemotherapy regimen with median OS (mOS) of 60 m in the ABC group vs 59.5 m in the PBC group. Notably, the addition of a BTKi to chemoimmunotherapy lead to a mOS of more than 10 years in BTKi-naïve pts compared to 5.1 years in BTKi-exposed pts and 1.8 years in pts who did not receive a BTKi for RS treatment. Conclusions: Patients who develop RS often have high risk CLL, especially complex cytogenetics. Although a large proportion of pts with RS respond to frontline therapy, almost half relapse. While mOS is similar for anthracycline and platinum-based chemotherapies, platinum-based chemotherapy can lead to superior CR and PFS. BTKi-naïve pts who receive a BTKi with chemotherapy for RS treatment have superior mOS.
In patients with COVID-19 receiving IMV or ECMO, adding baricitinib to usual care reduced all-cause mortality
Authors: Aditya Shah, John C. O’Horo
Journal: Annals of Internal Medicine (2022)

Source Citation Ely EW, Ramanan AV, Kartman CE, et al. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir Med. 2022;10:327-36. 35123660
Author Correction: Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth
Authors: Jiang-Sha Zhao, Shuo Shi, Hai-Yan Qu, Zuzana Keckesova, Zi-Jian Cao, Li-Xian Yang, Xiaofu Yu, Limin Feng, Zhong Shi, Joanna Krakowiak, Ruo-Ying Mao, Yi-Tong Shen, Yu-Meng Fan, Tian-Min Fu, Cunqi Ye, Daqian Xu, Xiaofei Gao, Jia You, Wenbo Li, Tingbo Liang, Zhimin Lu, Yu-Xiong Feng
Journal: Nature Metabolism (2022)
Management of checkpoint inhibitor toxicity and survival in patients with advanced melanoma.
Authors: Olivier Jules van Not, Rik Jasper Verheijden, Alfonsus Johannes Maria van den Eertwegh, John B. A. G. Haanen, Christian U. Blank, Maureen J.B. Aarts, Franchette Van Den Berkmortel, Jan Willem de Groot, Geke Hospers, Ellen Kapiteijn, Melissa Melanie de Meza, Djura Piersma, Rozemarijn Van Rijn, Marion Stevense - den Boer, Astrid Aplonia Maria Van Der Veldt, Gerard Vreugdenhil, Marye J. Boers-Sonderen, Willeke Blokx, Michel W.J.M. Wouters, Karijn Suijkerbuijk
Journal: Journal of Clinical Oncology (2022)

9546 Background: Management of checkpoint-inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of immunosuppressive treatment with anti-TNF on checkpoint-inhibitor efficacy. Methods: Advanced melanoma patients experiencing grade ≥3 irAEs after treatment with first-line ipilimumab-nivolumab between 2015 and 2021 were included from the Dutch Melanoma Treatment Registry. Progression-free survival (PFS), overall survival (OS) and melanoma-specific survival (MSS) were analyzed according to toxicity management regimen. A cox proportional hazards model was used to account for the confounders age, sex, performance status, lactate dehydrogenase, site of metastases and type of irAE. Results: Out of 771 ipilimumab-nivolumab treated patients, 350 were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids only and 115 received steroids with second-line immunosuppressants consisting of anti-TNF, mycophenolic acid, tacrolimus and other immunosuppressants. Median PFS was significantly longer for patients treated with steroids (11.3 months) than for patients treated with steroids and second-line immunosuppressants (5.4 months; HR 1.43; 95%CI 1.07-1.90; p = 0.01). Median OS was also significantly longer for the steroids group (46.1 months) than for the steroids and second-line immunosuppressants group (22.5 months; HR 1.64; 95%CI 1.16-2.32; p = 0.005). Results for MSS were similar (not reached versus 28.8 months; HR 1.70; 95%CI 1.16-2.49; p = 0.006). Median PFS, OS and MSS are shown in Table 1. After adjustment for potential confounders, patients treated with steroids + second-line immunosuppressants showed a non-significant trend towards a higher risk of progression (HR adj 1.40; 95%CI 1.00-1.97; p = 0.05), a higher risk of death (HR adj 1.54; 95%CI 1.03-2.30; p = 0.04) and of melanoma-specific death (HR adj 1.62; 95%CI 1.04-2.51; p = 0.032) compared to the steroids group. Conclusions: Second-line immunosuppression for irAEs is associated with impaired PFS, OS, and MSS in advanced melanoma patients treated with first-line ipilimumab-nivolumab, irrespective of being anti-TNF or other second-line immunosuppressants. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in melanoma but also in other tumor types. [Table: see text]
Encouraging efficacy of sintilimab combined with nanoparticle albumin-bound paclitaxel and platinum as the first-line treatment for metastatic esophageal squamous cell carcinoma: A retrospective study.
Authors: Chao-Jie Wang, Jiang-Shan Feng, Wei-Feng Zhao
Journal: Journal of Clinical Oncology (2022)

e16013 Background: Esophageal squamous cell carcinoma (ESCC) is one of the common malignancies worldwide and associated with poor prognosis. More recently, immunotherapy, especially monoclonal antibodies of programmed death receptor 1 (PD-1) and its ligand (PD-L1), has provided new treatment options for patients with various tumors. But there was no study to investigate the efficacy and safety of sintilimab combined with nanoparticle albumin-bound paclitaxel (Nab-PTX) and platinum as the first line treatment of metastatic ESCC. Methods: This was a retrospective study, the eligible metastatic ESCC patients were given sintilimab in combination with Nab-PTX and cisplatin or nedaplatin for up to 4-6 cycles (every 3 weeks). After immunochemtherapy, patients without progressive disease (PD) continued to receive sintilimab every three weeks as maintenance treatment until unacceptable toxicity, PD, withdrawal of consent, or for up to 2 years. The primary end point was objective response rate (ORR), the secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Results: A total of 22 patients diagnosed as metastatic ESCC were enrolled, one patient reached a complete response (CR), 15 patients reached a partial response (PR), 4 patients stable disease (SD) and 2 patients PD. The ORR was 72.7% (16/22), the DCR was 90.9% (20/22). The time to response (TTR) was 1.9 months (95% CI:1.7-2.2 months). The median PFS was 7.0 months (95% CI, 6.0-9.3 month), median OS was not reached (6.5 months to not reached). Treatment related adverse events (AEs) occurred in 21 patients (95.5%), and most of them were grade 1 and 2. AEs of grade 3 or 4 occurred in 10 (45.5%) patients, there was no treatment-related death in this study. Conclusions: The preliminary results of this study suggest that sintilimab combine with Nab-PTX and platinum for patients with metastatic ESCC had significant high ORR and encouraging median PFS, and the safety profile is manageable. Clinical trial information: ChiCTR2100051909.
Circulating tumor DNA (ctDNA) as a minimal residual disease (MRD) assessment and recurrence risk in patients undergoing curative intent resection with or without adjuvant chemotherapy in colorectal cancer: A systematic review and meta-analysis.
Authors: Anusha Chidharla, Eliot Rapoport, Kriti Agarwal, Brenda Linares, Sakti Chakrabarti, Anup Kasi
Journal: Journal of Clinical Oncology (2022)

3623 Background: Minimal residual disease (MRD) assessment may effectively detect cure in patients with colorectal cancer (CRC). Emerging data have suggested that circulating tumor DNA (ctDNA) can be a reliable biomarker for MRD in patients. Recent studies have shown the ability to detect MRD using ctDNA assay to assess recurrence risk and patient selection for adjuvant chemotherapy. We performed a systematic review and metanalysis of post operative ctDNA in Stage I-IV (oligometastatic) CRC patients after curative intent resection with or without adjuvant chemotherapy. Methods: We searched PubMed/Medline, EMBASE, Web of Science, Cochrane Library, and Google from inception to February 3, 2022 using keywords related to colorectal cancer, ctDNA, and MRD. The search also includes paper and conference presentations. The search resulted in 427 studies after removing the duplicates. Data were extracted to perform a meta-analysis using RevMan 5.4. software. Subsequent subgroup analysis was performed for stages I-III and oligometastatic stage IV CRC patients. Results: After the initial abstract screening, 48 studies were identified. The final review led to the inclusion of 27 studies representing 3459 patients with evaluable ctDNA, with 623 having +ve post-surgery ctDNA levels. Seven studies had analyses of patients specifically with oligometastatic disease, the rest 20 studies subdivided within stages I-III. The pooled HR for RFS in post-surgical ctDNA +ve vs -ve patients in all stages was 7.16 (95% CI 6.12-8.36) p &lt;0.00001. Subgroup analysis revealed pooled HR = 8.27 (95% CI 6.16-11.09) and 6.07 (95% CI 4.54-8.13) for stage I-III and IV CRC, respectively. Only 11 studies did analysis for post adjuvant chemotherapy patients based on ctDNA status. The pooled HR for RFS in post-adjuvant chemotherapy ctDNA +ve versus -ve patients in all stages was 12.40 (95% CI 9.24-16.64) p &lt;0.00001. Subgroup analysis revealed pooled HR = 13.95 (95% CI 9.08-21.43) and 11.39 (95% CI 5.99-21.66) for stage I-III and IV CRC, respectively. Conclusions: This is the largest and most current meta-analysis done on ctDNA levels as MRD assessment in CRC. Our analysis emphasizes that post operative ctDNA is a strong prognostic marker of RFS. Based on our results ctDNA can be a significant and independent predictor of RFS. Several ctDNA-based randomized adjuvant trials are ongoing internationally to confirm the clinical utility of ctDNA in colorectal cancer. [Table: see text]
KRAS wild-type pancreatic ductal adenocarcinoma: Molecular and therapeutic opportunities.
Authors: Aakash Desai, Daniel Walden, Thorvardur Ragnar Halfdanarson, Steven R Alberts, Robert R. McWilliams, Amit Mahipal, Daniel H. Ahn, Hani M. Babiker, Sri Harsha Tella, Patrick Walsh McGarrah, Sani Haider Kizilbash, Alex A. Adjei, Tanios S. Bekaii-Saab, Wen Wee Ma
Journal: Journal of Clinical Oncology (2022)

4130 Background: KRAS is mutationally activated in over 90% of pancreatic ductal adenocarcinoma (PDAC). Compared to pts with KRAS mutation, KRAS wild-type (wt) PDAC seem to have better response to therapy and may harbor potentially actionable molecular alterations. Here, we analyze the molecular profile and clinical outcome of a cohort of pts with KRAS wt PDAC. Methods: A retrospective review was conducted on pts with PDAC who underwent CLIA-certified Next Generation Sequencing (NGS) testing at Mayo Clinic between December 1, 2018 and December 1, 2021. Pts with KRAS wt PDAC with available reports were included. Their genomic drivers, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcome data were collected. The study was approved by the institutional IRB. Results: Of the 241 eligible pts, 8% (19) has KRAS wt PDAC. Among those, 2 pts had no mutation identified by the gene/molecular panel used. Of the 17 pts (89%) with identified alterations, mutations found in ³ 2 pts were TP53 (53%), CDKN2A (16%) and CDKN2B/ERBB2/PTEN/MSH3/RNF43/FBXW7/KMT2D/GNAS (11% each). Chromosomal rearrangements were identified in 5 (26%): CADPS2-BRAF, GP2-ERBB2, PTPRK-RSPO3, EML4-NTRK3 and TFG-MET. RNA expression results were available in 12 pts: common overexpression were ERBB2 (27%) and MET/NRAS/MYC/CCDN1/CCNE1/AR (18% each); and the under-expression MGMT (18%). Among the 13 pts with available MSI status via NGS, 2 (11%) were MSI-high (both had high TMB [28.4 and 23.7 m/MB]) while all others were TMB &lt; 10 m/MB. The median age at diagnosis was 61 years (68% males). 8/19 (42%) were Stage IV at diagnosis with 15/19 (79%) pts ultimately diagnosed with metastatic disease. Among metastatic pts, median lines of treatment received was 2.5 (range:0-4). 4 pts received FOLFIRINOX (FFX), 2 gemcitabine/ nab-paclitaxel (GP) and tumor response were comparable to previously reported results. 1 received 1 st -line pembrolizumab and remained on therapy at the time of analysis. The median length of follow up from diagnosis was 29 months. A patient with TFG-MET re-arrangement previously progressed on FFX and GP was treated using a MET inhibitor, and achieved significant CA19-9 drop and pancreas tumor shrinkage at 1 st restaging, with ongoing response. Conclusions: The molecular profile of KRAS wt PDAC is highly heterogeneous and difficult to generalize. Novel approaches (e.g., basket trials) are needed to develop therapy for this rare PDAC subgroup.
High-sensitivity C-reactive protein as prognostic and predictive marker in metastatic non-small cell lung carcinoma : A prospective single center study.
Authors: Debapriya Mondal, Sandip Ganguly, Joydeep Ghosh, Somnath Roy, Prashant Pandey, Deepak Dabkara, Reena Nair, Bivas Biswas
Journal: Journal of Clinical Oncology (2022)

e21101 Background: Systemic inflammation has been linked to incidence, progression, and poor outcomes in various cancers including non-small cell lung carcinoma (NSCLC). High-sensitivity CRP (hs-CRP) assays, generally used to assess cardiovascular risk, have rarely been evaluated in lung cancer studies. This study aimed to evaluate if baseline and on-treatment measurements of serum hs-CRP could provide prognostic and predictive information for patients with metastatic NSCLC treated with chemotherapy. Methods: In this single institutional prospective study 85 patients with metastatic NSCLC without targetable alterations who were treated with chemotherapy were included between 1st January 2020 and 31st December 2020, with a minimum follow-up duration of 6 months. Patients with coronary artery disease, active infections, autoimmune conditions, and chronic liver disease were excluded. Measurements of hs-CRP for all patients were done at baseline and every 12 weeks while on treatment. Patients were grouped by changes in hs-CRP levels compared to baseline levels as reduction (≥ 20% decline), and non-reduction (&lt; 20% decline) to assess association with radiologic response and progression- free survival (PFS). Results: Pre-treatment hs-CRP values were elevated for the majority (92.9% patients with ≥ 1 mg/L, 70.6% with ≥ 3 mg/L, and 42.3% with ≥ 10 mg/dL). No significant association was detected between the pre-treatment hs-CRP value and the number of metastatic sites (P = 0.4), histology (P = 0.3), or smoking status (P = 0.7). At a median follow-up of 13.7 months, the median PFS was 7.8 months (95% confidence interval [CI] 5.3 - 10.3). Patients with hs-CRP ≥10 mg/L had shorter PFS than those with hs-CRP &lt; 10 mg/L (Median PFS 7.5 months [95% CI 4.9 - 10] vs. 8.4 months [95% CI 0.1 - 17.4]; hazard ratio [HR] 1.8, 95% CI 1-3.4, P = 0.04). hs-CRP reduction (≥20% decline) after 12 weeks of treatment initiation predicted radiological response (P &lt; 0.001). Median PFS was 14.7 months (95% CI 7.4 – 22.1) in patients who demonstrated hs-CRP reduction (≥20% decline) at 12 weeks compared to 3.1 months (95% CI 2.3 – 3.9) in patients who did not (HR 0.17, 95% CI 0.08 - 0.33, P &lt; 0.001). Conclusions: Elevated hs-CRP at baseline was found to be a poor prognostic factor, while hs-CRP reduction by 20% or more on treatment predicted radiologic response and longer PFS in metastatic NSCLC patients treated with chemotherapy. Our findings of potential predictive and prognostic value of hs-CRP in metastatic NSCLC warrant validation in larger prospective studies.
Real-world evidence on predictors of survival for hormone-positive and triple-negative advanced breast cancer by treatment and <i>BRCA</i> status in the United States.
Authors: Dongmu Zhang, Leon Raskin, Wendy Sebby, Lei He, Sandeep Pawar, Steven A Narod, Olufunmilayo I. Olopade, Alexander Liede
Journal: Journal of Clinical Oncology (2022)

e18754 Background: Factors that affect overall survival (OS) for women with metastatic or recurrent breast cancer (BC) and BRCA1 or BRCA2 mutations (BRCA+) are a matter of debate. We analyzed electronic health records (EHR) from centers across the US to examine the effect of bilateral salpingo oophorectomy (BSO) and other factors on OS across treatment and molecular subtypes with emphasis on hormone-positive (HR+) and triple-negative BC (TNBC). Methods: A cohort of women diagnosed with stage 3 or 4 HR+ or TNBC from 1-Jan-2015 to 31-Dec-2019 was identified from EHR (Tempus Labs, Chicago, IL). BRCA+ was confirmed from medical notes and laboratory reports. A comparator group included HR+ and TNBC with no record of BRCA testing (Non-BRCA). Kaplan-Meier and Cox proportional hazards were used to evaluate predictors of OS from earliest diagnosis in multivariate models by BRCA status and molecular phenotype; treatment exposure (any time), mastectomy and BSO were treated as time-dependent variables. Results: We identified 1227 women with median age of 53 years (range 18-89) at BC diagnosis and median follow up of 26.1 months (max &gt; 26 years) and 358 deaths. Two-thirds had distant visceral or bone metastases, almost 60% were recurrent after original stage 1-3 BC; 302 women were stage 3 and 296 stage 4 at BC. The BRCA+ cohort included 439 women (195 BRCA1, 220 BRCA2, 24 “BRCA” mutation; 265 HR+, 142 TNBC) and median age at BC was 46 years (44 BRCA1, 47 BRCA2). Non-BRCA cohort consisted of 788 women with a median age of 57 at BC (378 HR+, 341 TNBC). BRCA+ had longer OS than non-BRCA ( P= 0.0001); HR+ had longer OS than TNBC ( P= 0.0001). For 331 TNBC, chemotherapeutic regimens were most common first line treatment; few (17%) received third line and 31% had no evidence of receiving systemic therapy. Age ≤50, BRCA+, and mastectomy were associated with increased OS in HR+; BRCA+ status and mastectomy were predictors of increased OS whereas platinum-based chemotherapy was associated with decreased OS in TNBC (Table). Across molecular subtypes, BSO was not an independent predictor of OS and most women (92%) had BSO after BC diagnosis. Conclusions: Regardless of BRCA status, women with advanced TNBC were almost exclusively treated with chemotherapy, which highlights the remaining unmet need for effective treatment options. Taking timing of BSO and other interventions into account is critical to understanding their effects of BC mortality.[Table: see text]